In the last funding period, we have performed a series of critical investigations that help to delineate the role of lithotripter shock wave (LSW) generated stress waves and cavitation in stone comminution;the mechanism of vascular injury in small blood vessels due to intraluminal bubble expansion;and the effect of treatment strategy on stone comminution and tissue injury in shock wave lithotripsy (SWL). Based on these important observations, we have developed two novel technologies, namely microsecond tandem pulse lithotripsy and in-situ pulse superposition, to improve stone comminution while reducing concomitantly collateral tissue injury in SWL. We have performed preliminary proof-of-principle experiments that demonstrate the validity of these new SWL technologies both in vitro and in vivo. Built on these accomplishments, we propose four new specific aims to further investigate the synergistic interaction between stress waves and cavitation, and to examine the effect of lateral spreading of residual fragments on overall stone comminution in SWL. We will also optimize the engineering design and system integration of an electromagnetic annular array (EMAA) shock wave generator, reflector inserts, and acoustic masks to customize the pressure waveform, distribution, and pulse sequence in an HM-3 lithotripter for effective treatment of kidney stones in various locations in the collection system. Our specific aims are as follows: Aim 1. Synergistic interaction between lithotripter generated stress waves and cavitation in stone comminution - the effect of lateral spreading of residual fragments on overall success of SWL. Aim 2. Development of an EMAA shock wave generator that can be integrated with an HM-3 lithotripter - exploring the full potential of microsecond tandem pulse lithotripsy. Aim 3. Optimization of pulse profile and beam size of an HM-3 lithotripter for the treatment of renal and upper ureteral stones. Aim 4. In vivo assessment of stone comminution and tissue injury produced by the optimized pulse profile, pressure distribution, and sequence in an upgraded HM-3 lithotripter. It is anticipated that the completion of these studies will provide a solid foundation for the rational use of existing clinical lithotripters and a platform for the development of innovative SWL technologies that can benefit all stone patients.